Fluvoxamine for the treatment of COVID-19
Authors: Hyun Kim, Shannon Manzi, Joseph Gonzelez-Heydrich, Jonathan Picker
Journal: The Lancet Global Health (2022)

We read with interest the investigation by Gilmar Reis and colleagues1Reis G Dos Santos Moreira-Silva EA Silva DCM et al.Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.Lancet Glob Health. 2022; 10: e42-e51Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar who studied the repurposing of fluvoxamine for the mitigation of hospitalisation risk among acutely symptomatic patients with COVID-19 in Brazil. Although impressive, their observation that a 10-day course of fluvoxamine resulted in an absolute risk reduction of 5% and a relative risk reduction of 32% for hospitalisations might be an underestimate of its potential efficacy. It is reasonable to believe that in order for fluvoxamine to exert a therapeutic benefit, it must reach a therapeutic systemic concentration, which is dependent on variables such as gastrointestinal absorption, hepatic function, renal function, and concomitant medications. However, one important variable that is not addressed in the paper is pharmacogenomic differences in CYP2D6, the enzyme primarily responsible for metabolic degradation of fluvoxamine. CYP2D6 is an important metabolic pathway for many pharmacologically significant substrates, including selective serotonin reuptake inhibitors such as fluvoxamine. Unlike other related genes, CYP2D6 exhibits clinically significant copy number variation resulting in some cases with an increased number of functional copies contributing to ultrarapid metabolic activity. Consequently, this directly effects bioavailability to such a degree that it is part of the determination for certain drug prescribing, as shown by guidelines from the Clinical Pharmacogenetics Implementation Consortium.2Hicks JK Bishop JR Sangkuhl K et al.Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors.Clin Pharmacol Ther. 2015; 98: 127-134Crossref PubMed Scopus (550) Google Scholar However, there are no clear fluvoxamine dosing recommendations for CYP2D6 ultrarapid metabolisers. In a genetically heterogeneous population such as Brazilians, genetic contributions from Native American, European, and African ancestries, could affect patients' responses to medications. It has been noted that the proportion of Brazilians with CYP2D6 duplications can be as high as 8·5%.3Friedrich DC Genro JP Sortica VA et al.Distribution of CYP2D6 alleles and phenotypes in the Brazilian population.PLoS One. 2014; 9e110691Crossref Scopus (39) Google Scholar Therefore, it is likely that of the 741 patients who received fluvoxamine in this study, approximately 63 patients might have had more than two functional copies of the gene, which could increase the likelihood of their being ultrarapid metabolisers. As a result, these patients might not have experienced therapeutic benefit due to faster metabolism of the drug, rendering their observed therapeutic responses closer to that of the placebo group. Because genetic variants in CYP2D6 would only be relevant in the active drug cohort, the net effect of not controlling for this variable would be to diminish the observed potential role of fluvoxamine. This study highlighted the prospect of repurposing of existing drugs in the battle against COVID-19. We believe that studying the contribution of pharmacogenomic variants in affecting therapeutic response to fluvoxamine may enhance the findings of this study. We declare no competing interests. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trialTreatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital. Full-Text PDF Open AccessFluvoxamine for the treatment of COVID-19We congratulate Gilmar Reis and colleagues (January, 2022)1 on their randomised, platform clinical trial (TOGETHER trial) investigating the effects of early treatment with fluvoxamine for patients with COVID-19. In the study, the impressive 5% absolute risk reduction in hospitalisation or prolonged emergency setting observation equates to a number needed to treat of 20, meaning for every 20 individuals treated, one will have this benefit from the treatment.1 At a US wholesale pharmacy cost of US$4·66, which equates to $93 (95%CI 56–285) to prevent one emergency setting visit or hospitalisation among all participants. Full-Text PDF Open AccessFluvoxamine for the treatment of COVID-19In the TOGETHER study,1 Gilmar Reis and colleagues showed a benefit of early treatment with fluvoxamine with notably a reduction in the need for hospitalisation, which was defined as retention in a COVID-19 emergency setting for more than 6 h or transfer to a tertiary hospital.1 The authors mentioned that the findings of their study, together with fluvoxamine's safety, tolerability, ease of use, low cost, and widespread availability, might influence national and international guidelines on the clinical management of COVID-19. Full-Text PDF Open AccessFluvoxamine for the treatment of COVID-19The clinical efficacy of fluvoxamine observed in the TOGETHER trial1 (although no change in virological outcomes was observed) might be related to anti-inflammatory effects via sigma-1 receptor agonism,2 but several other possible mechanisms warrant further investigation.3 Full-Text PDF Open AccessFluvoxamine for the treatment of COVID-19 – Author's replyWe are grateful for the communications pertaining to our trial.1 After publication, we noticed that some decision-making groups might not have the correct understanding of composite endpoints. Composite endpoint guidance is well-established. Strictly speaking, all clinical endpoints are a form of composite (eg, death can be from different reasons).2 If we apply the same composite endpoint (hospitalisation or emergency care >24 h) used in the paxlovid trial3 and molnupiravir trial,4 our effect size does not change importantly (relative risk [RR] 0·74 [95% CI 0·56–0·98]). Full-Text PDF Open Access